Hildebrand J D, Schaller M D, Parsons J T
Department of Microbiology, University of Virginia, Charlottesville 22908.
J Cell Biol. 1993 Nov;123(4):993-1005. doi: 10.1083/jcb.123.4.993.
The integrin family of heterodimeric cell surface receptors play critical roles in multiple biological processes by mediating cellular adhesion to the extracellular matrix (ECM). Adhesion triggers intracellular signaling cascades, including tyrosine phosphorylation and elevation of [Ca2+]i. The Focal Adhesion Kinase (FAK or pp125FAK), a protein tyrosine kinase that colocalizes with integrins in cellular focal adhesions, is a prime candidate for a mediator of integrin signaling events. Here we report an analysis of the domain structure of FAK in which we have identified a contiguous stretch of 159 amino acids within the COOH terminus essential for correct subcellular localization. When placed in the context of an unrelated cytosolic protein, this Focal Adhesion Targeting (FAT) sequence functions to efficiently mediate the focal adhesion localization of this fusion protein. Furthermore, this analysis suggests that pp125FAK cannot be activated oncogenically by mutation. This result could be explained if pp125FK either exhibits a narrow substrate specificity or is diametrically opposed by cellular phosphatases or other cellular processes.
异二聚体细胞表面受体的整合素家族通过介导细胞与细胞外基质（ECM）的黏附，在多种生物学过程中发挥关键作用。黏附会触发细胞内信号级联反应，包括酪氨酸磷酸化和细胞内钙离子浓度（[Ca2+]i）升高。粘着斑激酶（FAK或pp125FAK）是一种蛋白酪氨酸激酶，与整合素在细胞粘着斑中共定位，是整合素信号事件的主要介导因子候选者。在此，我们报告了对FAK结构域的分析，我们在其中鉴定出COOH末端一段连续的159个氨基酸，这对于正确的亚细胞定位至关重要。当置于不相关的胞质蛋白背景下时，这个粘着斑靶向（FAT）序列能够有效地介导这种融合蛋白的粘着斑定位。此外，该分析表明pp125FAK不能通过突变被致癌激活。如果pp125FK要么表现出狭窄的底物特异性，要么被细胞磷酸酶或其他细胞过程完全拮抗，那么这个结果就可以得到解释。
